V0162 a new long-acting bronchodilator for treatment of chronic obstructive lung diseases: preclinical and clinical results

Abstract

Background: Long acting bronchodilators are the standard of care in the management of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the efficacy and safety of V0162, a novel anticholinergic agent with bronchodilator properties, in preclinical models and in patients with COPD.

Methods: Guinea pigs were used to evaluate the impact of V0162 on the acetylcholine or histamine-induced bronchoconstriction. V0162 was also investigated in an allergic asthma model on ovalbumin-sensitized guinea pig. For clinical investigations, healthy volunteers were included in a dose-escalation, randomized, placebo-controlled phase I study to determine the maximal tolerated dose, followed by a randomized, placebo-controlled, cross-over phase II study in patients with COPD. V0162 was given via inhalation route. The objectives of the phase I/II study were to assess the safety and efficacy of V0162, in terms of bronchodilation and reduction in hyperinflation.

Results: Preclinical results showed that V0162 was able to prevent bronchoconstriction induced either by acetylcholine or histamine. V0162 reversed the bronchoconstriction and airway inflammation caused by ovalbumin challenge in sensitized guinea pigs. In the healthy volunteers study, 88 subjects were enrolled: 66 received V0162 and 22 received placebo. No particular safety concerns were raised. The maximal tolerated dose was not reached and the dose escalation was stopped at 2400 μg. A total of 20 patients with COPD were then enrolled. All patients received a single-dose of V0162 1600 μg and of placebo in two alternating periods. In COPD patients, V0162 demonstrated a significant increase in FEV1 compared with placebo (148 ± 137 ml vs. 36 ± 151 ml, p = 0.003). This bronchodilatory effect was corroborated by a reduction in hyperinflation. There was a trend toward dyspnea relief (change in visual analog scale at 22 h, -15.1 ± 26.0 mm vs.- 5.3 ± 28.8 mm with placebo, p = 0.054). No serious adverse events (AEs) were reported. Most common AEs were productive and non-productive cough, dyspnea and pruritus.

Conclusions: V0162 improved pulmonary function and tended to improve dyspnea in patients with COPD over more than 24 h. The slight plasmatic exposure observed might support the good safety profile.

Trial registration: ClinicalTrials.gov identifier: NCT01348555.

Fig. 1

Phase I and Phase II study design

Fig. 2

Bronchoprotection and anti-inflammatory effects of intratracheal V0162 single-dose in preclinical models. a Effect over time of V0162 and tiotropium on bronchoconstriction induced by acetylcholine in Guinea pigs, b Effect over time of V0162 and tiotropium on bronchoconstriction induced by histamine in Guinea pigs. Data are expressed as mean ± SEM. *p < 0.05 vs. vehicle (A and B, mixed model with treatment, as fixed factor and time as repeated measure. Baseline values were used as covariates). c Effect of V0162, tiotropium and budesonide on pulmonary resistance in ovalbumin-sensitized Guinea pigs. d Effect of V0162, tiotropium and budesonide on the total number of leukocytes in BAL performed 24 h post-challenge. Data are expressed as mean ± SEM. *p < 0.05 vs. vehicle (c and d, one-way ANOVA followed by a Dunn’s test)

Fig. 3

a Mean values and standard error (SE) of FEV_1, b mean values and SE of FVC, c mean values and SE of FRC, d change from baseline of dyspnea (VAS mm) over time (from 0 to 32 h) and SE, in placebo- and V0162-treated COPD patients. (V0162 1600 μg, n = 20)

Fig. 4

Mean plasma concentration over 72 h after a single dose of V0162 50 μg, 100 μg, 200 μg, 400 μg, 800 μg, 1200 μg, 1600 μg, 2000 μg, 2400 μg in healthy volunteers s (log/linear scale)